The site where the cathedral now stands was once a Spanish burial ground.  In 1828, the U.S. government recognized the right of the Church to this burial ground, though the title would not be officially clear for more than a century.  In September, 1833, the decision was reached to build the cathedral on that portion of land bounded by Dauphin, Conti, Claiborne and Franklin Streets.  Claude Beroujon drew up plans that year, and the building was completed and consecrated, after many financial setbacks, under Bishop Michael Portier, December 8, 1850.  The structure is of Roman Corinthian design and measures one hundred sixty-five feet in length by one hundred two feet in width.  The plans called for a tower on either side of the facade and a sixty foot portico between the towers, but these were not added until years later.  After Bishop Portier's death in May, 1859, John Quinlan, rector of the diocesan seminary at Cincinnati, was chosen as Mobile's second bishop and was installed in his cathedral church on December 11th.  Within two months Father James McGarahan, who acted as vicar-general, had written to a New Orleans foundry that a contract could be signed for the wrought iron fence costing $5000.  The priest's specifications called for "four pedestals of the four corners of the square... of the same size and pattern as those of the main gate, and finish each with a neat gas lamp."

During the War Between the States, the cathedral suffered no damage, as was the case with most of the City of Mobile.  However it did receive injury by the explosion of a munitions magazine in the harbor area fourteen blocks away on May 25, 1865, Ascension Thursday of that year.  Luckily it was about two hours before the hour of vespers, and the congregation had not yet arrived.